Chronopharmaceutics: Pharmaceutics Focused on Biological Rhythm

Abstract

INTRODUCTIONThe mammalian circadian pacemaker resides in the suprachiasmatic nuclei (SCN) and influences a multitude of biological processes, including the sleep-wake rhythm.1) The circadian clock acts like a multifunction timer to regulate homeostatic systems such as sleep and activity, hormone levels, appetite, and other bodily functions with 24 h cycles. Clock genes are identified as the genes that ultimately control a vast array of circadian rhythms in physiology and behavior.2)The individualization of pharmacotherapy has been performed mainly by monitoring drug concentrations. However, a pharmacogenetic approach such as genetic diagnosis has become a very attractive field due to the rapid progress of molecular biology.3) Consequently, dosage adjustment has been based on the interindividual differences in drug pharmacokinetics. However, intraindividual variability as well as interindividual variability should be considered in order to achieve further improvement of rational pharmacotherapy. This is because many drugs vary in potency and/or toxicity associated with the rhythmicity of biochemical, physiological and behavioral processes. [4][5][6][7][8] Theoretically, it has been argued that drug administration at certain times of the day should improve the outcome of pharmacotherapy.Biological rhythms not only impact the function of physiology, but also the pathophysiology of diseases. [4][5][6][7][8] Chronopharmacology is the investigative science that elucidates the biological rhythm dependencies of medications. The effectiveness and toxicity of many drugs vary depending on dosing time associated with 24 h rhythms of biochemical, physiological and behavioral processes under the control of circadian clock. Such chronopharmacological phenomena are influenced by not only the pharmacodynamics but also pharmacokinetics of medications. The knowledge of 24 h rhythm in the risk of disease plus evidence of 24 h rhythm dependencies of drug pharmacokinetics, effects, and safety constitutes the rationale for pharmacotherapy (chronotherapy). Chronotherapy is especially relevant in the following cases. [4][5][6][7][8] The risk and/or intensity of the symptoms of disease vary predictably over time as exemplified by allergic rhinitis, arthritis, asthma, myocardial infarction, congestive heart failure, stroke, and peptic ulcer disease. From the viewpoint of pharmaceutics, the application of biological rhythm to pharmacotherapy may be accomplished by the appropriate timing of conventionally formulated tablets and capsules, and special drug delivery systems to synchronize drug concentrations to rhythms in disease activity. 7) Pharmaceutical companies have focused on the investigation of underlying mechanisms as well as the conduct of multicenter clinical studies involving numerous patients with the purpose of devising chronotherapeutic interventions with a variety of medications. New technology for delivering medications precisely in a time-modulated fashion by bedside or ambulatory pumps is being developed to manage human dis...

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“…11,12,33,34 One strategy to increase the efficiency of pharmacotherapy is the administration of drugs at times at which they are most effective and/or best tolerated. Chronotherapy may be accomplished by the most appropriate timing of formulated tablets and capsules, and the DDS to synchronize drug concentrations to rhythms in disease state.…”